ICL-induced miR139-3pand miR199a-3phave opposite roles in hematopoietic cell expansion and leukemic transformation

Interstrand crosslinks (ICLs) are toxic DNA lesions that cause severe genomic damage during replication, especially in Fanconi anemia pathway-deficient cells. This results in progressive bone marrow failure and predisposes to acute myeloid leukemia (AML). The molecular mechanisms responsible for these defects are largely unknown. Using Ercc1-deficient mice, we show that Trp53is responsible for ICL-induced bone marrow failure and that loss of Trp53is leukemogenic in this model. In addition, Ercc1-deficient myeloid progenitors gain elevated levels of miR-139-3pand miR-199a-3pwith age. These microRNAs exert opposite effects on hematopoiesis. Ectopic expression of miR-139-3pstrongly inhibited proliferation of myeloid progenitors, whereas inhibition of miR-139-3pactivity restored defective proliferation of Ercc1-deficient progenitors. Conversely, the inhibition of miR-199a-3pfunctions aggravated the myeloid proliferation defect in the Ercc1-deficient model, whereas its enforced expression enhanced proliferation of progenitors. Importantly, miR-199a-3pcaused AML in a pre-leukemic mouse model, supporting its role as an onco-microRNA. Target genes include HuRfor miR-139-3pand Prdx6, Runx1, and Suz12for miR-199a-3p.The latter genes have previously been implicated as tumor suppressors in de novo and secondary AML. These findings show that, in addition to TRP53-controlled mechanisms, miR-139-3pand miR-199a-3pare involved in the defective hematopoietic function of ICL-repair deficient myeloid progenitors.